Aging is considered a leading risk factor for atherosclerosis, through mechanisms that remain unclear. Independent from traditional risk factors, aging appears to affect arterial wall structure in a manner believed to predispose to atherosclerosis. The goal of this project is to investigate mechanisms by which aging of the arterial wall contributes to atherosclerosis, and to develop an approach for studying the genes important to this process. One such gene encodes the tumor necrosis factor-a receptor-1 (TNFR1), which may mediate the enhanced proliferative responsiveness to TNF-a (TNF) observed in aortic smooth muscle cells from aged, as compared with young rats. Serum levels of TNF have been related to the risk of myocardial infarction and to the risk of mortality in aged patients. This project will test two hypotheses: (1) that aging of the arterial wall contributes to atherogenesis, independently of immune system aging; (2) that arterial wall TNF receptors contribute to atherogenesis, in a manner potentiated by or potentiating the aging effect. To test these hypotheses, we will perform carotid interposition grafting in young apolipoprotein E-deficient (Apoe-/-) mice, which develop carotid artery atherosclerosis. The grafts will be carotid arteries derived from congenic young and aged mice that are either (a) wild type or (b) TNFR1 -deficient. By comparing the atherosclerosis time course, extent, plaque cellular composition and selected molecular variables in these 4 groups, we will assess the role of arterial wall aging and TNFR1 in atherogenesis. To provide evidence for possible mechanisms underlying the effects of aging and TNFR1 on atherosclerosis, we will perform genome-wide transcriptional profiling on aortas from our carotid donor mice: young and aged, TNFR1- deficient and wild type. Thus, this project will (a) create a model system that can test whether arterial wall aging, by itself, contributes to atherogenesis; (b) elucidate the role of arterial wall TNFR1 in atherogenesis, both within and outside of the aging context; (c) create a comprehensive list of candidate genes that will facilitate devising mechanistic hypotheses to understand aging-dependent atherosclerosis-hypotheses that can be tested in our carotid graft system. In so doing, this project should build a foundation for identifying multiple arterial wall gene products that either contribute to or protect against atherosclerosis-predisposing effects of aging, and identify new therapeutic possibilities for atherosclerosis. [unreadable] [unreadable]